Chronic Inflammatory Pathologies Research Articles

The prevalence of the fungal flora in association with chronic inflammatory pathology of the larynx

The present article was designed to analyze the prevalence and clinical features of laryngomycosis associated with chronic inflammatory diseases of the larynx. We examined 430 patients suffering from chronic pharyngitis and found the fungal flora in 100 (23.2%) of them. Diagnostics of the fungal infection was performed by the microscopic study of the stained preparations (including the Gram method, Romanovskiy-Giemsa and fluorescent microscopy). The sowing on elective nutrient media was used. The study revealed the presence of yeast fungi (Candida) in 98 patients (98%) and mold fungi (Aspergillus) in the remaining two (2%). The hyperplastic form of fungal pharyngitis was diagnosed in 55% of the patients. We have identified the following predisposing factors for fungal laryngitis: the gastroesophageal reflux disease in 56% of the patients, smoking in 50%, the long-term use of the removable dentures with the inadequate care for them in 30%, and the consistent use of inhaled corticosteroids in 27%. Hyperglycemia was documented in 6% and the history of long-term treatment with antibiotics in in 10% of the patients. The scheme for the combined antifungal therapy has been developed. Its practical application allowed to achieve the eradication of the fungal flora and to improve the clinical course of chronic laryngitis in 75% of the patients.

Involvement of Ly6C, 4-1BB, and KLRG1 in the activation of lamina propria lymphocytes in the small intestine of sanroque mice

Roquin is an E3 ligase that regulates mRNA stability. Mice with a mutation in the Rc3h1 gene and Roquin protein, referred to as Roquinsan/san or sanroque mice, develop broad-spectrum chronic inflammatory conditions and autoimmune pathologies. Our laboratory recently reported that sanroque mice also develop extensive inflammation that is localized in the small intestine but is rare in the colon. Here, we demonstrate that small intestinal intraepithelial lymphocytes (IELs) are present in the epithelium of sanroque mice but that cell recoverability is low using standard extraction techniques even though lamina propria lymphocytes (LPLs) can be recovered in normal numbers. In studies aimed at characterizing T cell costimulatory markers and activation molecules on LPLs in sanroque mice, we identified Ly6C and 4-1BB (CD137) as being expressed at elevated levels on sanroque small intestinal LPLs, and we show that both of those subsets, in conjunction with cells expressing the KLRG1 T cell activation molecule, are sources of IL-17A, IFN-γ, and TNFα. TNFα was primarily produced by 4-1BB+, KLRG1-cells, but was also made by some 4-1BB-, KLRG1-cells, and 4-1BB-, KLRG1+ cells. These findings collectively suggest that the small intestinal inflammatory response in sanroque mice is driven, at least in part, by LPL activation through Ly6C and 4-1BB signaling, and they provide further evidence in support of using the sanroque mouse as an animal model of chronic small intestinal inflammation.

IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice.

IL-6 trans-signaling, and not IL-6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL-6 trans-signaling, rather than total inhibition of IL-6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL-6 classic signaling-driven protective immune responses. (Hepatology 2017;65:89-103).

Role of CT Mastoids in the Diagnosis and Surgical Management of Chronic Inflammatory Ear Diseases.

Chronic Suppurative Otitis Media (CSOM) is a chronic inflammation of middle ear cleft. It presents with discharging ear and decreased hearing. The diagnosis is mostly on clinical examination with otoscope or oto endoscope. Computerised Tomography (CT) of mastoids is done to evaluate the extent of the disease and its complication. High resolution CT is now the investigation of choice for temporal bone disease. This study emphasizes on the importance of CT scan in diagnosis of inflammatory ear diseases and most importantly identifying pitfalls or complications which a surgeon can come across during surgery. The aims and objectives of this study is (1) to establish the efficacy of CT in the diagnosis of the complications and surgical management of chronic inflammatory pathologies of middle ear. (2) To find subgroups of CSOM where CT is particularly useful. In this series, a total of 25 cases presenting to our OPD at Govt. ENT Hospital between 2013 and 2014 have been diagnosed and findings of surgery correlated with HRCT scan of temporal bones done preoperatively. In this study, 64% of the patients were male and incidence of CSOM with patients undergoing surgery belonged to the age group 21-30years (32%). The most common presenting symptom was ear discharge (92%) and decreased hearing (96%). The most common type of pathology in this study was attic perforation (36%) and granulations (40%) followed by cholesteatoma (36%) and mucosal edema (16%). Not all cases presented with complications, facial palsy (12%) and mastoid abscess (8%) were among few complications seen. 14 patients (56%) of 25 cases underwent simple cortical mastoidectomy followed by 9 cases (36%) for modified radical mastoidectomy and atticotomy for 2 cases (8%). CT scan findings correlated well with surgical findings for cholesteatoma, middle ear mass and bone erosions. Where as for ossicular integrity and facial canal dehiscence, there was a discrepancy.

Divergent JAM-C Expression Accelerates Monocyte-Derived Cell Exit from Atherosclerotic Plaques

Atherosclerosis, caused in part by monocytes in plaques, continues to be a disease that afflicts the modern world. Whilst significant steps have been made in treating this chronic inflammatory disease, questions remain on how to prevent monocyte and macrophage accumulation in atherosclerotic plaques. Junctional Adhesion Molecule C (JAM-C) expressed by vascular endothelium directs monocyte transendothelial migration in a unidirectional manner leading to increased inflammation. Here we show that interfering with JAM-C allows reverse-transendothelial migration of monocyte-derived cells, opening the way back out of the inflamed environment. To study the role of JAM-C in plaque regression we used a mouse model of atherosclerosis, and tested the impact of vascular JAM-C expression levels on monocyte reverse transendothelial migration using human cells. Studies in-vitro under inflammatory conditions revealed that overexpression or gene silencing of JAM-C in human endothelium exposed to flow resulted in higher rates of monocyte reverse-transendothelial migration, similar to antibody blockade. We then transplanted atherosclerotic, plaque-containing aortic arches from hyperlipidemic ApoE-/- mice into wild-type normolipidemic recipient mice. JAM-C blockade in the recipients induced greater emigration of monocyte-derived cells and further diminished the size of atherosclerotic plaques. Our findings have shown that JAM-C forms a one-way vascular barrier for leukocyte transendothelial migration only when present at homeostatic copy numbers. We have also shown that blocking JAM-C can reduce the number of atherogenic monocytes/macrophages in plaques by emigration, providing a novel therapeutic strategy for chronic inflammatory pathologies.

Palmitoylethanolamide Modulates Inflammation-Associated Vascular Endothelial Growth Factor (VEGF) Signaling via the Akt/mTOR Pathway in a Selective Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α)-Dependent Manner.

Background and AimAngiogenesis is emerging as a pivotal process in chronic inflammatory pathologies, promoting immune infiltration and prompting carcinogenesis. Ulcerative Colitis (UC) and Crohn’s Disease (CD) represent paradigmatic examples of intestinal chronic inflammatory conditions in which the process of neovascularization correlates with the severity and progression of the diseases. Molecules able to target the angiogenesis have thus the potential to synergistically affect the disease course. Beyond its anti-inflammatory effect, palmitoylethanolamide (PEA) is able to reduce angiogenesis in several chronic inflammatory conditions, but no data about its anti-angiogenic activity in colitis have been produced, yet.MethodsThe effects of PEA on inflammation-associated angiogenesis in mice with dextran sulphate sodium (DSS)-induced colitis and in patients with UC were assessed. The release of Vascular Endothelial Growth Factor (VEGF), the hemoglobin tissue content, the expression of CD31 and of phosphatidylinositol 3-kinase/Akt/mammalian-target-of-rapamycin (mTOR) signaling axis were all evaluated in the presence of different concentrations of PEA and concomitant administration of PPAR-α and -γ antagonists.ResultsOur results demonstrated that PEA, in a selective peroxisome proliferator activated receptor (PPAR)-α dependent mechanism, inhibits colitis-associated angiogenesis, decreasing VEGF release and new vessels formation. Furthermore, we demonstrated that the mTOR/Akt axis regulates, at least partly, the angiogenic process in IBD and that PEA directly affects this pathway.ConclusionsOur results suggest that PEA may improve inflammation-driven angiogenesis in colonic mucosa, thus reducing the mucosal damage and potentially affecting disease progression and the shift towards the carcinogenesis.

Resilience of the intestinal microbiota following pathogenic bacterial infection is independent of innate immunity mediated by NOD1 or NOD2

The innate immune receptors, NOD1 and NOD2, are key regulators of intestinal homeostasis. NOD2 deficiency is linked to increased risk for Crohn's disease, a type of inflammatory bowel disease characterized by chronic inflammatory pathology and dysbiosis within resident microbial communities. However, the relationship between NOD protein-regulated immune functions and dysbiosis remains unclear. We hypothesized that the relationship between NOD1 or NOD2 deficiency and altered community structure during chronic disease may arise via NOD-dependent impairment of community resilience over time. Using the Salmonella ΔaroA model of chronic colitis with littermate mice to control for environmental influences on the microbiota, we show that NOD proteins exert a relatively minor impact on the chronic inflammatory environment and do not significantly contribute to bacterial abundance or community resilience following infection. Rather, temporal shifts in relative abundance of targeted bacterial groups correlated with inflammatory phenotype driven by presence of the pathogen and the ensuing complex immune response.

A bacterial-biofilm-induced oral osteolytic infection can be successfully treated by immuno-targeting an extracellular nucleoid-associated protein.

Periodontal disease exemplifies a chronic and recurrent infection with a necessary biofilm component. Mucosal inflammation is a hallmark response of the host seen in chronic diseases, such as colitis, gingivitis, and periodontitis (and the related disorder peri-implantitis). We have taken advantage of our recently developed rat model of human peri-implantitis that recapitulates osteolysis, the requirement of biofilm formation, and the perpetuation of the bona fide disease state, to test a new therapeutic modality with two novel components. First we used hyperimmune antiserum directed against the DNABII family of proteins, now known to be a critical component of the extracellular matrix of bacterial biofilms. Second we delivered the antiserum as cargo in biodegradable microspheres to the site of the biofilm infection. We demonstrated that delivery of a single dose of anti-DNABII in poly(lactic-co-glycolic acid) (PLGA) microspheres induced significant resolution of experimental peri-implantitis, including marked reduction of inflammation. These data support the continued development of a DNABII protein-targeted therapeutic for peri-implantitis and other chronic inflammatory pathologies of the oral cavity in animals and humans.

Influence des hormones stéroïdes sur la production de deux marqueurs inflammatoires, l’IL-12 et le monoxyde d’azote, au cours de la maladie de Behçet

Uveitis is one of the major diagnostic criteria of Behçet's disease (BD), a chronic systemic inflammatory pathology with an uncertain etiology. Since uveitis is more frequent in male patients, we assessed the level and the effect of sex hormones on inflammatory responses during BD. Peripheral blood was taken from 19 patients with BD and 20 healthy subjects. Estradiol, testosterone and cortisol were measured in plasma by ELISA. Circulating mononuclear cells (PBMC) were obtained on gradient density and cultured with or without the three hormones for 24h at 37̊C. IL-12 and nitric oxide (NO) were measured in vivo and ex vivo by ELISA and a modified Griess method, respectively. We confirmed the significantly higher in vivo and in vitro levels of NO and IL-12 in BD in comparison to controls (P<0.05). We also found that circulating cortisol was lower in BD while sex hormones did not show any significant difference between the groups (P>0.05). In vitro, NO was reduced by estradiol and cortisol and increased by testosterone in both sexes. In contrast, while IL-12 production showed the same production profile as NO in women, estradiol and cortisol failed to reduce IL-12 levels in men. Our results may explain in part the differences observed between men and women in disease clinical expression. In fact, male patients seem to have defective IL-12 down-regulation by estradiol and cortisol that increases Th1 immune responses. This may be implicated in the severe expression of BD in men.

PRMT5-Mediated Methylation of NF-κB p65 at Arg174 Is Required for Endothelial CXCL11 Gene Induction in Response to TNF-α and IFN-γ Costimulation.

Inflammatory agonists differentially activate gene expression of the chemokine family of proteins in endothelial cells (EC). TNF is a weak inducer of the chemokine CXCL11, while TNF and IFN-γ costimulation results in potent CXCL11 induction. The molecular mechanisms underlying TNF plus IFN-γ-mediated CXCL11 induction are not fully understood. We have previously reported that the protein arginine methyltransferase PRMT5 catalyzes symmetrical dimethylation of the NF-κB subunit p65 in EC at multiple arginine residues. Methylation of Arg30 and Arg35 on p65 is critical for TNF induction of CXCL10 in EC. Here we show that PRMT5-mediated methylation of p65 at Arg174 is required for induction of CXCL11 when EC are costimulated with TNF and IFN-γ. Knockdown of PRMT5 by RNAi reduced CXCL11 mRNA and protein levels in costimulated cells. Reconstitution of p65 Arg174Ala or Arg174Lys mutants into EC that were depleted of endogenous p65 blunted TNF plus IFN-γ-mediated CXCL11 induction. Mass spectrometric analyses showed that p65 Arg174 arginine methylation is enhanced by TNF plus IFN-γ costimulation, and is catalyzed by PRMT5. Chromatin immunoprecipitation assays (ChIP) demonstrated that PRMT5 is necessary for p65 association with the CXCL11 promoter in response to TNF plus IFN-γ. Further, reconstitution of p65 Arg174Lys mutant in EC abrogated this p65 association with the CXCL11 promoter. Finally, ChIP and Re-ChIP assays revealed that symmetrical dimethylarginine-containing proteins complexed with the CXCL11 promoter were diminished in p65 Arg174Lys-reconstituted EC stimulated with TNF and IFN-γ. In total, these results indicate that PRMT5-mediated p65 methylation at Arg174 is essential for TNF plus IFN-γ-mediated CXCL11 gene induction. We therefore suggest that the use of recently developed small molecule inhibitors of PRMT5 may present a therapeutic approach to moderating chronic inflammatory pathologies.

Antioxidant and Anti-Inflammatory Properties of Widely Consumed Date Palm (Phoenix Dactylifera L.) Fruit Varieties in Algerian Oases

The purpose of this study was to estimate the antioxidant and anti-inflammatory activities of methanolic extracts of date palm fruits grown in Algeria. Four in vitro methods were employed to evaluate the antioxidant activity (AA), namely β-carotene-linoleic acid system, phosphomolybdenum method, 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity and Ferric-Reducing Antioxidant Power assay. The anti-inflammatory activity was carried out using carrageenan-induced edema model. The extracts were found to be a rich source of polyphenols, flavonoids and flavonols. The methanolic extract of Ali Ourached cultivar showed the highest AA for the four methods cited previously (76.85%, 90.25 μmol of ascorbic acid/g of extract, 206 µg/mL and 56.04 μmol Fe (II) ∕ 100 g DW, respectively). Anti-inflammatory findings revealed noticeable reduction of paw volume ranging from 35.64 to 67.56% as a response to oral administration of 250 mg/kg dose of methanolic extracts. This study constitutes an endeavor for understanding the bioactive phytochemical variability in date palm fruit cultivars and corresponding antioxidant and anti-inflammatory activities. Practical Applications In this study, the biological potentials of methanolic extracts of date palm fruits (Phoenix dactylifera L.) were evaluated. The date cultivars could potentially be considered as a functional food and could be useful as a good source of natural antioxidant compounds with possible applications to reduce oxidative stress and treatment of chronic inflammatory pathologies. The results suggest that date palm fruits contain potent antioxidant and anti-inflammatory properties that can find application in food science, food technology and nutrition.

New Imaging in Gastrointestinal Tract.

Pathologies of gastrointestinal tract are various and affect patients of different ages. Both of these conditions influence the imaging modalities of gastrointestinal tract that underwent relevant changes during recent years. Magnetic Resonance (MR) and Computed Tomography (CT) techniques, optimised for gastrointestinal imaging, are playing today an increasing role in the evaluation of gastrointestinal disorders, and several studies have shown the advantage of these techniques over tradition barium fluoroscopic examinations secondary to improvements in spatial and temporal resolution combined with improved bowel distending agents. Based on recent literature and guidelines, there is a change of paradigms regarding the diagnosis of esophagus and gastrointestinal cancer towards CT, whereas for small bowel imaging in inflammatory disease MRI with a new focus on Diffusion Weighted Imaging (DWI) are the most important imaging modalities, because DWI can be easily implemented in standard MRI for routine use to further enhance the diagnostic accuracy in disease assessment [1–4]. CT and MRI play an important role also in functional disorders. In particular, the recent development of faster MRI pulse sequences provides rapid, real-time imaging of the gastrointestinal tract, pinpointing areas of stricture and providing valuable information on motility. This special issue is devoted to current and emerging techniques in gastrointestinal tract, focusing on some selected topics that are both interesting and challenging: neoplastic pathologies, chronic inflammatory diseases, functional pathologies, and nontraumatic emergency causing occlusion. The first section covers cross-sectional imaging of the gastrointestinal tract in neoplastic disease, including lymphoma, both through a review (“Radiological Features of Gastrointestinal Lymphoma” by G. Lo Re et al.) and through an original paper (“Staging of Primary Abdominal Lymphomas: Comparison of Whole-Body MRI with Diffusion-Weighted Imaging and 18F-FDG-PET/CT” by A. Stecco et al.) and small-bowel neoplasms (“Small-Bowel Neoplasms: Role of MRI Enteroclysis” by A. Faggian et al.). The imaging of hepatocellular carcinoma after locoregional treatments is also reviewed (“CT Appearance of Hepatocellular Carcinoma after Locoregional Treatments: A Comprehensive Review” by D. Marin et al.). Cross-sectional imaging modalities are fundamental also in the management of patients with inflammatory bowel disease (IBD) from the first diagnosis and throughout the entire course of the disease. In this sense, MRI, owing to the lack of ionizing radiation, represents the main technique in young patients with IBD who may require multiple studies over a lifetime. New imaging of chronic inflammatory pathologies is focused on Crohn's disease, where the imaging is essential also in scoring the activity of disease (“3D-EAUS and MRI in the Activity of Anal Fistulas in Crohn's Disease” by M. E. Alabiso et al.; “Assessment of Disease Activity in Small Bowel Crohn's Disease: Comparison between Endoscopy and Magnetic Resonance Enterography Using Mria and Modified Mria Score” by A. Scardapane et al.). Some functional pathologies are also discussed: achalasia and pelvic floor disfunction (“Imaging in the Evaluation of Endoscopic or Surgical Treatment for Achalasia” by D. Palladino et al.; “MR Imaging in Diagnosis of Pelvic Floor Descent: Supine versus Sitting Position” by F. Iacobellis et al.). Finally nontraumatic emergency causing occlusion is discussed in three different papers, with emphasis on the role of MDCT and dynamic MRI (“Intussusception in Adults: The Role of MDCT in the Identification of the Site and Cause of Obstruction” by V. Valentini et al.; “A Novel Diagnostic Aid for Detection of Intra-Abdominal Adhesions to the Anterior Abdominal Wall Using Dynamic Magnetic Resonance Imaging” by D. Randall et al.; “Adhesions to Mesh after Ventral Hernia Mesh Repair are Detected by MRI but Are Not a Cause of Long Term Chronic Abdominal Pain” by O. Langbach et al.). The contributions of this special issue could stimulate the spread of new imaging modalities in daily practice, pinpoint technical aspects, and share some strategies to optimise CT and MR protocols. Roberto Grassi Antonio Pinto Lorenzo Mannelli Daniele Marin Maria Antonietta Mazzei

Diabetes and Periodontal Diseases: An Established Two-Way Relationship

Background: Periodontal diseases (PD), including periodontitis, are chronic inflammatory pathologies caused by bacteria in the subgingival biofilm which affect the periodontal tissues. PD is now considered a localized, chronic, oral infection that activates the host immuno-inflammatory responses both locally and systemically, and also constitutes a source of bacteraemia. It is a known fact that periodontal diseases exercise an important influence on the pathogenesis of numerous systemic diseases, including diabetes mellitus (DM). In the mid-nineties, sufficient scientific evidence emerged to confirm an association between DM and periodontitis, which then began to be regarded as the sixth complication of DM. Current scientific evidence points to a two-way relationship between DM and periodontal disease, whereby DM is associated with an increase in the incidence and progression of periodontitis, while periodontal infection is associated with worsening glycemic control in diabetic patients. This two-way relationship points to a need to promote oral health in DM patients, and to implement a joint management protocol between endocrinologist and dentist that aims to create adequate conditions for early diagnosis and the effective treatment of both diseases.

Chronic Inflammatory Diseases: Progress and Prospect with Herbal Medicine.

Diseases associated with chronic inflammatory pathology claim a major share of worldwide deaths each year. A principal reason behind the huge number of casualties is associated with mild or unnoticed symptoms for long period of time since the outset, and that specific treatment options for these diseases have not yet emerged. Current anti-inflammatory drugs essentially have become ineffective for long term protection from these diseases as they also interfere with essential cellular pathways and associated toxicities. Notably, recent studies with a number of phytochemicals have shown promising results. These compounds isolated from various medicinal plants express their anti-inflammatory activities by down regulating expression of several crucial pro-inflammatory mediators. These are mostly antioxidants; inhibit induction of key transcription factors like nuclear factor kappa B (NF-κB) that are responsible for expression of proinflammatory mediators, and other growth regulators. Definitely, some of these compounds have the potential to be developed into new therapeutic agents to better control inflammation associated diseases in near future. This review summarizes recent findings on the molecular mechanisms through which various inflammatory activities are linked to disease progression and a group of natural products that have shown promise in controlling these processes.

The p47phox deficiency significantly attenuates the pathogenicity of Chlamydia muridarum in the mouse oviduct but not uterine tissues

The Chlamydia muridarum induction of the upper genital tract pathology in mice has been used to investigate the mechanisms of chlamydial pathogenesis. We report that the NCF1 (neutrophil cytosolic factor1)-encoded p47phox (phagocyte oxidase), an essential subunit of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, contributes significantly to C. muridarum induction of hydrosalpinx. Mice lacking p47phox (p47phox-deficient) were no longer able to develop significant hydrosalpinx following an intravaginal infection with C. muridarum. However, there was no significant difference in uterine horn dilation (as a result of the endometrial glandular duct dilation) between the p47phox-deficient and -sufficient mice. Thus, the role of NADPH oxidase in chlamydial pathogenesis is restricted to the oviduct tissue rather than the entire upper genital tract. Interestingly, both the p47phox-deficient and -sufficient mice displayed similar levels of chlamydial live organism shedding from the lower genital tract, suggesting that the NADPH oxidase is not required for the mouse control of chlamydial infection in the lower genital tract. Furthermore, the p47phox deficiency did not affect the infectious organism burden in the upper genital tract tissues, indicating that the NADPH-oxidase activity is not necessary for the mouse prevention of chlamydial ascension from the lower to upper genital tracts. However, the p47phox-defieicnt mice displayed a significantly reduced chronic inflammatory infiltration in the oviduct but not uterine tissues, supporting the finding that the NADPH oxidase activity is required for chlamydial induction of dilation in the oviduct but not the endometrial glandular duct. Thus, we have demonstrated a significant role of the host NADPH oxidase in promoting chronic inflammatory pathology in the oviduct following chlamydial infection.

Activation of autophagy in macrophages by pro-resolving lipid mediators

The resolution of inflammation is an active process driven by specialized pro-resolving lipid mediators, such as 15-epi-LXA4 and resolvin D1 (RvD1), that promote tissue regeneration. Macrophages regulate the innate immune response being key players during the resolution phase to avoid chronic inflammatory pathologies. Their half-life is tightly regulated to accomplish its phagocytic function, allowing the complete cleaning of the affected area. The balance between apoptosis and autophagy appears to be essential to control the survival of these immune cells within the inflammatory context. In the present work, we demonstrate that 15-epi-LXA4 and RvD1 at nanomolar concentrations promote autophagy in murine and human macrophages. Both compounds induced the MAP1LC3-I to MAP1LC3-II processing and the degradation of SQSTM1 as well as the formation of MAP1LC3+ autophagosomes, a typical signature of autophagy. Furthermore, 15-epi-LXA4 and RvD1 treatment favored the fusion of the autophagosomes with lysosomes, allowing the final processing of the autophagic vesicles. This autophagic response involves the activation of MAPK1 and NFE2L2 pathways, but by an MTOR-independent mechanism. Moreover, these pro-resolving lipids improved the phagocytic activity of macrophages via NFE2L2. Therefore, 15-epi-LXA4 and RvD1 improved both survival and functionality of macrophages, which likely supports the recovery of tissue homeostasis and avoiding chronic inflammatory diseases.

Smoking-Induced Expression of the GPR15 Gene Indicates Its Potential Role in Chronic Inflammatory Pathologies

Despite the described clear epigenetic effects of smoking, the effect of smoking on genome-wide gene expression in the blood is obscure. We therefore studied the smoking-induced changes in the gene-expression profile of the peripheral blood. RNA was extracted from the whole blood of 48 individuals with a detailed smoking history (24 never-smokers, 16 smokers, and 8 ex-smokers). Gene-expression profiles were evaluated with RNA sequencing, and results were analyzed separately in 24 men and 24 women. In the male smokers, 13 genes were statistically significantly (false-discovery rate<0.1) differentially expressed; in female smokers, 5 genes. Although most of the differentially expressed genes were different between the male and female smokers, the G-protein-coupled receptor 15 gene (GPR15) was differentially expressed in both male and female smokers compared with never-smokers. Analysis of GPR15 methylation identified significantly greater hypomethylation in smokers compared with that in never-smokers. GPR15 is the chemoattractant receptor that regulates T-cell migration and immunity. Up-regulation of GPR15 could explain to some extent the health hazards of smoking with regard to chronic inflammatory diseases.

Vaccination of Children with recurrent and chronic inflammatory ENT pathology

Recommendations highlighted features vaccination of children with with recurrent and chronic inflammatory ENT pathology. It is shown how the immunization scheme may be changed according to the pathology and the age of the child.

Psychedelics and Immunomodulation: Novel Approaches and Therapeutic Opportunities.

Classical psychedelics are psychoactive substances, which, besides their psychopharmacological activity, have also been shown to exert significant modulatory effects on immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and cell survival via activating NF-κB and mitogen-activated protein kinases. Recently, several neurotransmitter receptors involved in the pharmacology of psychedelics, such as serotonin and sigma-1 receptors, have also been shown to play crucial roles in numerous immunological processes. This emerging field also offers promising treatment modalities in the therapy of various diseases including autoimmune and chronic inflammatory conditions, infections, and cancer. However, the scarcity of available review literature renders the topic unclear and obscure, mostly posing psychedelics as illicit drugs of abuse and not as physiologically relevant molecules or as possible agents of future pharmacotherapies. In this paper, the immunomodulatory potential of classical serotonergic psychedelics, including N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine, and 3,4-methylenedioxy-methamphetamine will be discussed from a perspective of molecular immunology and pharmacology. Special attention will be given to the functional interaction of serotonin and sigma-1 receptors and their cross-talk with toll-like and RIG-I-like pattern-recognition receptor-mediated signaling. Furthermore, novel approaches will be suggested feasible for the treatment of diseases with chronic inflammatory etiology and pathology, such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer’s disease.

Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation.

Lipid overload in obesity and type 2 diabetes is associated with adipocyte dysfunction, inflammation, macrophage infiltration, and decreased fatty acid oxidation (FAO). Here, we report that the expression of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in mitochondrial FAO, is higher in human adipose tissue macrophages than in adipocytes and that it is differentially expressed in visceral vs. subcutaneous adipose tissue in both an obese and a type 2 diabetes cohort. These observations led us to further investigate the potential role of CPT1A in adipocytes and macrophages. We expressed CPT1AM, a permanently active mutant form of CPT1A, in 3T3-L1 CARΔ1 adipocytes and RAW 264.7 macrophages through adenoviral infection. Enhanced FAO in palmitate-incubated adipocytes and macrophages reduced triglyceride content and inflammation, improved insulin sensitivity in adipocytes, and reduced endoplasmic reticulum stress and ROS damage in macrophages. We conclude that increasing FAO in adipocytes and macrophages improves palmitate-induced derangements. This indicates that enhancing FAO in metabolically relevant cells such as adipocytes and macrophages may be a promising strategy for the treatment of chronic inflammatory pathologies such as obesity and type 2 diabetes.